Manifestations Of Disease Research Articles

Clinical and multimodal imaging features of adult-onset neuronal intranuclear inclusion disease.

This study aimed to analyze the clinical and multimodal imaging manifestations of adult-onset neuronal intranuclear inclusion disease (NIID) patients and to investigate NIID-specific neuroimaging biomarkers. Forty patients were retrospectively enrolled from the Qilu Hospital of Shandong University. We analyzed the clinical and imaging characteristics of 40 adult-onset NIID patients and investigated the correlation between these characteristics and genetic markers and neuropsychological scores. We further explored NIID-specific alterations using multimodal imaging indices, including diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), and brain age estimation. In addition, we summarized the dynamic evolution pattern of NIID by examining the changes in diffusion weighted imaging (DWI) signals over time. The NIID patients' ages ranged from 31 to 77 years. Cognitive impairment was the most common symptom (30/40, 75.0%), while some patients (18/40, 45.0%) initially presented with episodic symptoms such as headache (10/40, 25.0%). Patients with cognitive impairment symptoms had more cerebral white matter damage (χ2 = 11.475, P = 0.009). The most prevalent imaging manifestation was a high signal on DWI in the corticomedullary junction area, which was observed in 80.0% (32/40) of patients. In addition, the DWI dynamic evolution patterns could be classified into four main patterns. Diffusion tensor imaging (DTI) revealed extensive thinning of cerebral white matter fibers. The estimated brain age surpassed the patient's chronological age, signifying advanced brain aging in NIID patients. The clinical manifestations of NIID exhibit significant variability, usually leading to misdiagnosis. Our results provided new imaging perspectives for accurately diagnosing and exploring this disease's neuropathological mechanisms.

Protective Non-neutralizing anti-N-terminal Domain mAb Maintains Fc-mediated Function against SARS-COV-2 Variants up to BA.2.86-JN.1 with Superfluous InVivo Protection against JN.1 Due to Attenuated Virulence.

Substantial evidence supports that Fc-mediated effector functions of anti-spike Abs contribute to anti-SARS-Cov-2 protection. We have previously shown that two non-neutralizing but opsonic mAbs targeting the receptor-binding domain and N-terminal domain (NTD), Ab81 and Ab94, respectively, are protective against lethal Wuhan SARS-CoV-2 infection in K18-hACE2 mice. In this article, we investigated whether these protective non-neutralizing Abs maintain Fc-mediated function and Ag binding against mutated SARS-CoV-2 variants. Ab81 and Ab94 retained their nanomolar affinity and Fc-mediated function toward Omicron and its subvariants, such as BA.2, BA.4, BA.5, XBB, XBB1.5, and BQ1.1. However, when encountering the more heavily mutated BA.2.86, Ab81 lost its function, whereas the 10 new mutations in the NTD did not affect Ab94. In vivo experiments with Ab94 in K18-hACE2 mice inoculated with a stringent dose of 100,000 PFU of the JN.1 variant revealed unexpected results. Surprisingly, this variant exhibited low disease manifestation in this animal model with no weight loss or death in the control group. Still, assessment of mice using a clinical scoring system showed better protection for Ab94-treated mice, indicating that Fc-mediated functions are still beneficial. Our work shows that a protective anti-receptor-binding domain non-neutralizing mAb lost reactivity when BA.2.86 emerged, whereas the anti-NTD mAb was still functional. Finally, this work adds new insight into the evolution of the SARS-CoV-2 virus by reporting that JN.1 is substantially less virulent invivo than previous strains.

Connections Between Hypertension, Atherosclerosis, Acute Myocardial Infarction, and Risk of Dementia

As the percentage of geriatric patients continues to increase in both the United States and globally, the prevalence of both cardiovascular disease and dementia continues to climb. Both dementia and cardiovascular disease are devastating diseases that impose a significant burden economically, socially, and medically on both a local and systemic level. The most common fatal manifestation of cardiovascular disease is acute myocardial infarction, responsible for death in more than 80% of patients with cardiovascular disease. Prominent risk factors for acute myocardial infarction including hypertension and atherosclerosis have been independently associated with an increased risk for cognitive decline and all-cause dementia and Alzheimer disease, separate from vascular dementia. Acute myocardial infarction itself has also been independently associated with an increased incidence of all-cause dementia and Alzheimer disease. It is based on the connection between acute myocardial infarction, its major risk factors, and the incidence of dementia that it is of importance to define and explore the potential role that therapies for these conditions, as well as acute myocardial infarction itself, may play in mitigating the risk of dementia onset and severity. In this review, we assess current therapeutics that exist for atherosclerosis, hypertension and acute myocardial infarction that have been demonstrated to reduce later risk of dementia, and explore the mechanism that underlies the association between the incidence of acute myocardial infarction and the risk of dementia.

Chronic inflammation: Cross linking insights from Ayurvedic Sciences, a silver lining to systems biology and personalized medicine

Precision in personalized medicine is a crucial subject that needs comprehensive discussion and scientific validation. Traditional healthcare approaches like the Ayurvedic Sciences are often contextually linked with personalized medicine. However, it is unfortunate that this knowledge concerning Ayurveda and personalized medicine is restricted to applying systems biology techniques to 'prakriti' the phenotypic expression and characterization detailed in the literature. There are other significant constructs besides prakruti that interest an Ayurvedic physician, which accounts for crafting precision in evidence-based medicinal practices. There is this influential model of Ayurvedic healthcare practice wherein the physician maps specific personalized characters in addition to prakruti to deduce the host responses to endogenous and exposome conditions. Subsequently, tailored protocols are administered that bring about holistic, personalized outcomes.The review aimed to determine the effective methods for integrating Systems Biology, Ayurvedic Sciences, and Personalized Medicine (precision medicinebased). Ayurveda adopts a holistic approach, considering multiple variables and their interconnections, while the modern reductionist approach focuses on understanding complex details of smaller parts through rigorous experimentation. Despite seeming extremes, ongoing research on lifestyle, gut health, and spiritual well-being highlights the evolving intersection between traditional Ayurvedic practices and modern science. The current focus is on developing the fundamental concept of Ayurveda Biology by incorporating Systems Biology techniques.Challenges in this integration include understanding diverse data types, bridging interdisciplinary knowledge gaps, and addressing technological limitations and ethical concerns. Overcoming these challenges will require interdisciplinary collaboration, innovative methodologies, substantial investment in technology, and cultural sensitivity to preserve Ayurveda's core principles while leveraging modern scientific advancements. The focus of discussions and debates on such collaborations should be breakthrough clinical models, such as chronic inflammation, which can be objectively related to specific stages of disease manifestations described in Ayurveda. Validating patient characteristics with systems biology approaches, particularly in shared pathologies like chronic inflammation, is crucial for bringing prediction and precision to personalized medicine

Analysis of bacteraemia caused by group C and G Streptococcus (Streptococcus dysgalactiae subsp. equisimilis) in Western Sydney over a 6-year period (2015-2020).

Streptococcus dysgalactiae subsp. equisimilis (SDSE) has increasingly been recognised as a significant pathogen that causes a myriad of infections, ranging from cellulitis to invasive infections, including bacteraemia and even toxic shock syndrome. The aim of this study was to examine the epidemiology and disease manifestations of bacteraemia caused by SDSE. We retrospectively reviewed cases of SDSE bacteraemia in adults aged ≥ 18 years admitted to four public hospitals in Western Sydney, Australia, between January 2015 and December 2020. We reviewed demographics, comorbidities, disease manifestations, management, and outcomes. There were 108 patients with SDSE bacteraemia over a six-year period. The median age of individuals with SDSE bacteraemia was 70 years (interquartile range, IQR, 58-85 years). Cardiovascular disease (46%), chronic skin conditions (44%) and diabetes (37%) were the most common comorbidities. Ten patients (9%) with SDSE bacteraemia had healthcare-acquired infections. Skin and skin structure infections (SSTIs) were the most common presentations (59%), while bone and joint infections (BJIs) represented 13% of the cases. Twenty patients (19%) had septic shock on presentation. Fifteen patients (14%) were prescribed clindamycin, while one patient received intravenous immunoglobulin (IVIg). Infective endocarditis (IE) was present in 3% of patients; however, only 44% of the total patients had an echocardiogram. The 30-day mortality rate was 13%, but it was greater in those aged > 75 years (21%). The average length of hospital stay for patients who survived was 15 days, and the average duration of intravenous therapy was 12 days. SDSE bacteraemia is typically a community-onset infection with a fifth of patients in our cohort presenting with septic shock. Though complications such as BJI (13%) and IE (3%) are infrequent, 30-day mortality is high at 21% in those aged > 75 years.

Elucidating the causal nexus and immune mediation between frailty and chronic kidney disease: integrative multi-omics analysis

Background Empirical research has consistently documented the concurrent manifestation of frailty and chronic kidney disease (CKD). However, the existence of a reverse causal association or the influence of confounding variables on these correlations remains ambiguous. Methods Our analysis of 7,078 participants from National Health and Nutrition Examination Survey(NHANES) (1999–2018) applied weighted logistic regression and Mendelian Randomization (MR) to investigate the correlation between the frailty index (FI) and renal function. The multivariate MR analysis was specifically adjusted for type 2 diabetes and hypertension. Further analysis explored 3282 plasma proteins to link FI to CKD. A two-step network MR highlighted immune cells’ mediating roles in the FI-CKD relationship Result Genetically inferred FI and various renal function markers are significantly correlated, as supported by NHANES analyses. Multivariate MR analysis revealed a direct causal association between the FI and CKD. Additionally, our investigation into plasma proteins identified Tmprss11D and MICB correlated with FI and CKD, respectively. A two-step network MR to reveal 15 immune cell types, notably Central Memory CD4+ T cells and Lymphocytes, as crucial mediators between FI and CKD. Conclusion Our work establishes a causal connection between frailty and CKD, mediated by specific immune cell profiles. These findings highlight the importance of immune mechanisms in the frailty-CKD interplay and suggest that targeting shared risk factors and immune pathways could improve management strategies for these conditions. Our research contributes to a more nuanced understanding of frailty and CKD, offering new avenues for intervention and patient care in an aging population.

Anesthetic management in orthopaedic surgery for rheumatic patients

Patients with rheumatic diseases frequently require orthopaedic surgeries due to progressive joint damage and deformities. These patients pose unique challenges for anesthesiologists due to systemic involvement, altered anatomy, and chronic pain management needs. This review explores optimal anesthetic strategies to improve surgical outcomes and enhance patient safety in this vulnerable population. Preoperative assessment is crucial for identifying systemic manifestations of rheumatic diseases, including cardiovascular, respiratory, and renal involvement, which can significantly impact anesthetic management. A thorough evaluation helps tailor the anesthetic plan to individual patient needs, ensuring better perioperative care.Regional anesthesia, particularly neuraxial blocks and peripheral nerve blocks, offers significant benefits over general anesthesia in this population. These techniques can reduce postoperative pain, enhance recovery times, and decrease opioid consumption. However, the presence of spinal deformities and anticoagulation therapy in these patients requires careful consideration and meticulous planning. Multimodal analgesia, combining regional techniques with systemic medications, is recommended to manage chronic pain and minimize opioid use postoperatively. Effective pain management strategies are essential for improving postoperative outcomes and patient satisfaction.

Association between fetal hemoglobin, lactate dehydrogenase, and disease severity in patients with sickle cell disease at Bugando Medical Centre, Mwanza, Tanzania.

There is a wide range of clinical manifestations in sickle cell disease (SCD). Despite having the same condition, each person's response to disease complications differs greatly. Individuals can be categorized according to the severity of their diseases to determine which group they fall into and receive the appropriate care based on their needs. The relationship between fetal hemoglobin (HbF), lactate dehydrogenase (LDH), and disease severity in Tanzania is little understood. This investigation sought to ascertain the relationship between HbF, LDH, and disease severity in SCD patients at the Bugando Medical Center. This cross-sectional study was carried out on SCD patients aged 6 months and older at the Bugando Medical Center in Mwanza, Tanzania. A total of 130 SCD patients were enrolled. The clinical history and laboratory test results for SCD patients were recorded on a specially constructed patient report form. The majority of participants (56.9%) were men. For the population under study, more than half (60.8%) of participants had a moderate clinical phenotype (MCP), followed by 31.5% of asymptomatic participants and 7.7% of people with severe clinical phenotypes (SCP). Participants with SCP had substantially higher levels of LDH, with a mean level of 810.97IU/L (95% CI: 559.31-1062.64) and a p-value of 0.005. The severe clinical phenotype exhibited a significantly higher mean HbF score value of 10.09% (95% CI: 7.44-13.74%) with a p-value of 0.024 when compared to the asymptomatic and moderate clinical phenotypes. In SCD patients with SCP compared to ACP and MCP, the HbF levels were higher, but did not show a protective effects, and LDH can be used to predict the severity of SCD.

Unraveling the differential mechanisms of revascularization promoted by MSCs & ECFCs from adipose tissue or umbilical cord in a murine model of critical limb-threatening ischemia

BackgroundCritical limb-threatening ischemia (CLTI) constitutes the most severe manifestation of peripheral artery disease, usually induced by atherosclerosis. CLTI patients suffer from high risk of amputation of the lower extremities and elevated mortality rates, while they have low options for surgical revascularization due to associated comorbidities. Alternatively, cell-based therapeutic strategies represent an effective and safe approach to promote revascularization. However, the variability seen in several factors such as cell combinations or doses applied, have limited their success in clinical trials, being necessary to reach a consensus regarding the optimal “cellular-cocktail” prior further application into the clinic. To achieve so, it is essential to understand the mechanisms by which these cells exert their regenerative properties.Herein, we have evaluated, for the first time, the regenerative and vasculogenic potential of a combination of endothelial colony forming cells (ECFCs) and mesenchymal stem cells (MSCs) isolated from adipose-tissue (AT), compared with ECFCs from umbilical cord blood (CB-ECFCs) and AT-MSCs, in a murine model of CLTI.MethodsBalb-c nude mice (n:32) were distributed in four different groups (n:8/group): control shams, and ischemic mice (after femoral ligation) that received 50 µl of physiological serum alone or a cellular combination of AT-MSCs with either CB-ECFCs or AT-ECFCs. Follow-up of blood flow reperfusion and ischemic symptoms was carried out for 21 days, when mice were sacrificed to evaluate vascular density formation. Moreover, the long-term molecular changes in response to CLTI and both cell combinations were analyzed in a proteomic quantitative approach.ResultsAT-MSCs with either AT- or CB-ECFCs, promoted a significant recovery of blood flow in CLTI mice 21 days post-ischemia. Besides, they modulated the inflammatory and necrotic related processes, although the CB group presented the slowest ischemic progression along the assay. Moreover, many proteins involved in the repairing mechanisms promoted by cell treatments were identified.ConclusionsThe combination of AT-MSCs with AT-ECFCs or with CB-ECFCs promoted similar revascularization in CLTI mice, by restoring blood flow levels, together with the modulation of the inflammatory and necrotic processes, and reduction of muscle damage. The protein changes identified are representative of the molecular mechanisms involved in ECFCs and MSCs-induced revascularization (immune response, vascular repair, muscle regeneration, etc.).

Rheumatoid meningitis in the absence of rheumatoid arthritis: 2 cases

Rheumatoid meningitis (RM) is a rare extra-articular manifestation of rheumatoid arthritis (RA) that has been increasingly recognized by neurologists. However, the diversity of its clinical manifestations makes its diagnosis difficult. RM does not have a unified diagnostic standard, and its link with RA needs to be studied further. Here we report two cases of RM without a history of RA. The first patient, an 80-year-old woman, presented with sudden unilateral limb weakness, with brain MR showing abnormal signals in the leptomeningeal of the right frontal parietal. Subarachnoid hemorrhage was excluded after imaging examination, and infectious meningitis was ruled out after cerebrospinal fluid (CSF) examination. The patient was diagnosed as having RM, she had increased levels of CCP and AKA, the markers of RA, but no history of the disease or other clinical manifestations of it. Another case, a 65-year-old man, was hospitalized with Bell’s palsy. We found that he had intracranial imaging changes highly consistent with those characteristic of RM during his routine examination. Except for the left peripheral facial palsy, the patient had no other neurological signs or symptoms and no RA history. After a careful physical examination, we found no joint or other manifestations or serological abnormalities consistent with RA (RF, CCP, AKA, etc.). However, after excluding infection meningitis and considering the patient’s unique imaging results, we diagnosed him as having RM. We report these two cases as references for clinical diagnosis and treatment of RM, providing a discussion of our rationale.

Immune dysregulation due to bi-allelic mutation of the actin remodeling protein DIAPH1

Children with severe inflammatory diseases are challenging to diagnose and treat, and the etiology of disease often remains unexplained. Here we present DIAPH1 deficiency as an unexpected genetic finding in a child with fatal inflammatory bowel disease who also displayed complex neurological and developmental phenotypes. Bi-allelic mutations of DIAPH1 were first described in patients with a severe neurological phenotype including microcephaly, intellectual disability, seizures, and blindness. Recent findings have expanded the clinical phenotype of DIAPH1 deficiency to include severe susceptibility to infections, placing this monogenic disease amongst the etiologies of inborn errors of immunity. Immune phenotypes in DIAPH1 deficiency are largely driven aberrant lymphocyte activation, particularly the failure to form an effective immune synapse in T cells. We present the case of a child with a novel homozygous deletion in DIAPH1, leading to a premature truncation in the Lasso domain of the protein. Unlike other cases of DIAPH1 deficiency, this patient did not have seizures or lung infections. Her major immune-related clinical symptoms were inflammation and enteropathy, diarrhea and failure to thrive. This patient did not show T or B cell lymphopenia but did have dramatically reduced naïve CD4+ and CD8+ T cells, expanded CD4-CD8- T cells, and elevated IgE. Similar to other cases of DIAPH1 deficiency, this patient had non-hematological phenotypes including microcephaly, developmental delay, and impaired vision. This patient’s symptSoms of immune dysregulation were not successfully controlled and were ultimately fatal. This case expands the clinical spectrum of DIAPH1 deficiency and reveals that autoimmune or inflammatory enteropathy may be the most prominent immunological manifestation of disease.

Esophageal Lichen Planus: The Efficacy and Safety of Tacrolimus in Reducing Inflammation and Need for Dilation.

Esophageal Lichen Planus (ELP) is a rare inflammatory disease most seen in middle-aged Caucasian women, manifested by sloughing mucosa, thick exudate, and proximal strictures. Most case reports and small series highlight using steroids and other immunosuppressants. To our knowledge, oral tablet tacrolimus has not been studied. We aimed to assess the change in ELP after oral tacrolimus treatment. The primary outcome was the efficacy of tacrolimus objectively through our scoring system, ELPSS. All consecutive adults with ELP who underwent more than one EGD by two esophagologists and being treated with tacrolimus or other treatment were eligible for inclusion in this retrospective cohort study. Inflammation and fibrostenotic disease were graded using the novel ELP Severity Score (ELPSS). Twenty two patients met the inclusion criteria. Half (11) received tacrolimus (dose 1-2 mg BID) and half (11) received other therapy (i.e. cyclosporine, topical steroids, or none). Mean ELPSS on first EGD, extraesophageal manifestations of disease, presenting symptoms, and baseline characteristics were similar between groups. Among patients on Tac vs No-Tac, there was a statistically significant improvement in ELPSS (mean difference 1.8 pts; 95% CI 0.25-3.38; P=0.02). Response rate was 89% with Tac vs 30% with No-Tac (P=0.025). All 22 patients underwent bougie dilation safely with a mean diameter of 16 mm achieved. Patients on Tac also required less frequent dilation. Oral tablet tacrolimus reduced the inflammatory and fibrostenotic components of ELP. Thus, low-dose oral tacrolimus is safe and should be considered in patients with more severe disease.

Effect of copper nanoparticles green-synthesized using Ocimum basilicum against Pseudomonas aeruginosa in mice lung infection model

Abstract The frequency of lung infection induced by multi-drug resistant strains of Pseudomonas aeruginosa has significantly risen, primarily due to the inadequate effectiveness of powerful chemotherapeutic methods. This study demonstrates that the Ocimum basilicum aqueous extract and copper nanoparticles (CuNPs) exhibited significant antioxidant and anti-infectious properties under in vivo conditions. To analyze the characteristics of the CuNPs synthesized from the reaction between copper nitrate solution and the aqueous O. basilicum extract, various techniques such as energy dispersive X-ray analysis, field emission scanning electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction analysis, and transmission electron microscopy were employed. The in vivo study encompasses the assessment of P. aeruginosa lethal dose in mice and the disease manifestation analysis, which comprises reduction in body weight, hypothermia, bacteremia, and other parameters, over a 48 h infection period. The infected mice exhibited a notable decrease in body temperature, measuring at 25°C after 48 h, compared to the initial temperature of 39°C. Additionally, a 30% reduction in weight was seen at the conclusion of the study. To assess the effectiveness of CuNPs on lung infection caused by the calculated lethal dose and bacteremia, histopathology analysis was employed. The bacterial load in the CuNPs group was determined to be 0.5 Log10CFU/mL on Day 8, indicating a notable decrease from the initial measurement of 1.5 Log10CFU/mL on Day 1. The histopathological findings revealed a widespread and sporadic buildup of alveolar space inflammatory cells, with infiltrates observed throughout all lung sections in infected mice. Enhanced lung histology was observed in the group of animal treated with reduced exudates noted at 200 µg/kg. CuNPs demonstrated inhibitory effects on the growth of P. aeruginosa at 8 µg/mL, while at 16 µg/mL, they effectively eradicated P. aeruginosa. The research unequivocally demonstrates the efficacy of CuNPs extract in combating lung infections induced by P. aeruginosa at 200 µg/kg. The recent survey aims to further explore the biomedical characteristics of these CuNPs in order to develop a powerful treatment against this dangerous pathogen.

Ocular manifestations in ANCA-associated vasculitis: a comprehensive analysis from Chinese medical centers.

This study aimed to explore ocular manifestations in ANCA-associated vasculitis (AAV), focusing on granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis (MPA) and to examine the associations with laboratory parameters and other systemic manifestations. This retrospective study reviewed data from 533 AAV patients across two major Chinese medical centers from January 2016 to November 2023. Data including diagnosis, cranial manifestations of disease, ocular complications, and laboratory parameters were analyzed. Univariate and multivariable logistic regression analyses assessed associations across disease manifestations. Machine learning models were also utilized to predict the risk of retinal/eye involvement in AAV patients. Among 533 patients (210 GPA, 217 MPA, 99 EGPA, and 7 unclassified AAV), ocular complications were observed in 20.64% of them, with a distribution of 36.67% in GPA, 7.37% in MPA, and 18.18% in EGPA. The most common ocular manifestations included scleritis and retro-orbital mass/dacryocystitis, which were notably prevalent in GPA patients. Retinal involvement was observed in 9.09% of EGPA cases. The machine learning models yielded that eosinophil percentage (EOS%), high-sensitivity C-reactive protein (hsCRP), and CD4 + T cell/CD8 + T cell ratio (T4/T8) can predict retinal involvement. Furthermore, the white blood cell, EOS%, APTT, IgA, hsCRP, PR3-ANCA, and T4/T8 can predict eye involvement. Ocular manifestations are a prevalent complication across all forms of AAV. Predictive models developed through machine learning offer promising tools for early intervention and tailored patient care. This necessitates a multidisciplinary approach, integrating rheumatology and ophthalmology expertise for optimal patient outcomes.

Cutaneous Involvement by Refractory Celiac Disease Type 2 Histologically Mimicking Mycosis Fungoides.

Refractory celiac disease (RCD) is a rare condition characterized by persistent malabsorptive symptoms and villous atrophy despite a gluten-free diet. While RCD type 1 has a normal intraepithelial lymphocyte phenotype, RCD type 2 is defined by the presence of immunophenotypically aberrant and monoclonal intraepithelial T lymphocytes, with a high propensity to transform to enteropathy-associated T-cell lymphoma (EATL). Although dermatological manifestations of celiac disease are common, presentation with cutaneous involvement by abnormal lymphocytes of RCD type 2 or EATL is rare, with few histologic descriptions in the literature. We describe the case of a 66-year-old man with a history of celiac disease presenting with a generalized, erythematous papular rash over his torso, upper arms, and legs. Biopsy of his skin lesions showed prominent hyperkeratosis with underlying spongiosis and interface change. Increased intraepithelial (epidermotropic) lymphocytes were observed, out of proportion to the level of spongiosis, but not overly atypical in appearance. Immunohistochemistry revealed an aberrant T-cell immunophenotype (CD3/2/7 positive; CD5/4/8 negative), raising suspicion for a cutaneous T-cell lymphoproliferative disorder. A duodenal biopsy demonstrated total villous atrophy with a morphologically bland population of epitheliotropic T lymphocytes showing the same aberrant immunophenotype. Similar cells were also identified by flow cytometry in the peripheral blood. In conjunction with the history of celiac disease, a diagnosis of RCD type 2 or 'EATL in situ' with cutaneous involvement was made. Cutaneous RCD type 2 or EATL should be considered as differential diagnoses in patients with a history of celiac disease and histopathology reminiscent of epidermotropic forms of cutaneous T-cell lymphoma.

Primary Cutaneous Diffuse Large B‑Cell Lymphoma, Leg Type: A Clinical Case

Introduction. Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type it is a rare variant of skin lymphoma that has an aggressive course and a high risk of extracutaneous manifestations.The purpose of this work is to familiarize a wide range of specialists with the clinical manifestations of a rare disease — primary cutaneous diffuse large B-cell lymphoma.Materials and methods. An interesting clinical case is presented and the medical history of a patient with B-cell lymphoma from the skin is analyzed.Results. A differential diagnosis of the disease was made. Based on the study of histological material, the final clinical diagnosis was established and further treatment tactics were determined.Discussion. The patient had spots and plaques on the lower extremities, the sole visible signs of the disease. These symptoms may suggest a positive prognosis and a gradual progression. Diagnostic measures should include gathering medical history, assessing the local condition, and carrying out an excision biopsy early in the examination process for an accurate and prompt diagnosisConclusion. Due to the rarity of this subtype of lymphoma and the limited number of domestic publications on the topic, a more detailed study and description of individual clinical cases can lead to a better understanding of the characteristics of the symptoms and the processes of pathological changes in cells, tissues, and organs. This could potentially lead to the development of more efficient methods for early diagnosis and timely treatment of the condition.

G0-PCC-FISH derived multi-parametric biodosimetry methodology for accidental high dose and partial body exposures

High dose radiation exposures are rare. However, medical management of such incidents is crucial due to mortality and tissue injury risks. Rapid radiation biodosimetry of high dose accidental exposures is highly challenging, considering that they usually involve non uniform fields leading to partial body exposures. The gold standard, dicentric assay and other conventional methods have limited application in such scenarios. As an alternative, we propose Premature Chromosome Condensation combined with Fluorescent In-situ Hybridization (G0-PCC-FISH) as a promising tool for partial body exposure biodosimetry. In the present study, partial body exposures were simulated ex-vivo by mixing of uniformly exposed blood with unexposed blood in varying proportions. After G0-PCC-FISH, Dolphin’s approach with background correction was used to provide partial body exposure dose estimates and these were compared with those obtained from conventional dicentric assay and G0-PCC-Fragment assay (conventional G0-PCC). Dispersion analysis of aberrations from partial body exposures was carried out and compared with that of whole-body exposures. The latter was inferred from a multi-donor, wide dose range calibration curve, a-priori established for whole-body exposures. With the dispersion analysis, novel multi-parametric methodology for discerning the partial body exposure from whole body exposure and accurate dose estimation has been formulated and elucidated with the help of an example. Dose and proportion dependent reduction in sensitivity and dose estimation accuracy was observed for Dicentric assay, but not in the two PCC methods. G0-PCC-FISH was found to be most accurate for the dose estimation. G0-PCC-FISH has potential to overcome the shortcomings of current available methods and can provide rapid, accurate dose estimation of partial body and high dose accidental exposures. Biological dose estimation can be useful to predict progression of disease manifestation and can help in pre-planning of appropriate & timely medical intervention.

Distinct neurodevelopmental and epileptic phenotypes associated with gain- and loss-of-function GABRB2 variants

Variants in GABRB2, encoding the β2 subunit of the γ-aminobutyric acid type A (GABAA) receptor, can result in a diverse range of conditions, ranging from febrile seizures to severe developmental and epileptic encephalopathies. However, the mechanisms underlying the risk of developing milder vs more severe forms of disorder remain unclear. In this study, we conducted a comprehensive genotype-phenotype correlation analysis in a cohort of individuals with GABRB2 variants. Genetic and electroclinical data of 42 individuals harbouring 26 different GABRB2 variants were collected and accompanied by electrophysiological analysis of the effects of the variants on receptor function. Electrophysiological assessments of α1β2γ2 receptors revealed that 25/26 variants caused dysfunction to core receptor properties such as GABA sensitivity. Of these, 17 resulted in gain-of-function (GOF) while eight yielded loss-of-function traits (LOF). Genotype-phenotype correlation analysis revealed that individuals harbouring GOF variants suffered from severe developmental delay/intellectual disability (DD/ID, 74%), movement disorders such as dystonia or dyskinesia (59%), microcephaly (50%) and high risk of early mortality (26%). Conversely, LOF variants were associated with milder disease manifestations. Individuals with these variants typically exhibited fever-triggered seizures (92%), milder degrees of DD/ID (85%), and maintained ambulatory function (85%). Notably, severe movement disorders or microcephaly were not reported in individuals with loss-of-function variants. The data reveals that genetic variants in GABRB2 can lead to both gain and loss-of-function, and this divergence is correlated with distinct disease manifestations. Utilising this information, we constructed a diagnostic flowchart that aids in predicting the pathogenicity of recently identified variants by considering clinical phenotypes. This work was funded by the Australian National Health & Medical Research Council, the Novo Nordisk Foundation and The Lundbeck Foundation.

Inflammatory Giant Cell Carcinoma of the Lung: Clinicopathologic, Immunohistochemical, and Next-generation Sequencing Study of 14 Cases.

A distinctive histological variant of poorly differentiated, sarcomatoid, non-small cell lung carcinoma characterized by a discohesive population of giant tumor cells associated with prominent interstitial inflammatory cell infiltrates is described. The tumors occurred in 7 women and 7 men, 42 to 72 years of age (mean: 56y). They predominantly affected the upper lobes and measured 1.3 to 9cm in greatest diameter (mean: 4.6cm). The tumor cells were characterized by large pleomorphic nuclei with prominent nucleoli, ample cytoplasm, and frequent abnormal mitoses, and were surrounded by a dense inflammatory cell infiltrate, often associated with emperipolesis. Immunohistochemical stains were positive in the tumor cells for cytokeratin AE1/AE3 and CK8/18 and negative for TTF1, napsin A, p40, and CK5/6. Next-generation sequencing was performed in all cases using the Oncomine Precision Assay; the most common abnormalities found included TP53 mutations (9 cases) and AKT1 amplification (8 cases), followed by KRAS mutations (4 cases) and MAP2K1/2 mutations (4 cases). Clinical follow-up was available in 13 patients. Three patients presented with metastases as the initial manifestation of disease; 8 patients died of their tumors from 6 months to 8 years (mean: 2.7y); 3 patients were alive and well from 4 to 6 years; and 2 patients had metastases when last seen but were lost to follow-up thereafter. The importance of recognizing this distinctive and aggressive variant of non-small cell lung carcinoma lies in avoiding confusion with a sarcoma or other types of malignancy.

Routine Coronary Angiography and Functional Cardiac Tests before Resection of Abdominal Aortic Aneurysm in Patients without Symptoms of Myocardial Infarction

INTRODUCTION: Cardiac complications are leaders in the structure of mortality of patients after resection of abdominal aortic aneurysms (AAA). In recent years more data have been obtained on the possibility of performing invasive coronary angiography (CAG) as a method of preoperative assessment of the condition of the coronary arteries. AIM: To assess the tactics of routine CAG and preventive revascularization of the myocardium in comparison with non-invasive functional tests in patients without clinical manifestations of coronary heart disease (CHD) from positions of the hospital outcomes of AAA resections. MATERIALS AND METHODS: A retrospective study included 205 patients without clinical and instrumental signs of CHD who underwent AAA resection at National Medical Research Center of Surgery named after A. Vishnevsky in 2001–2021. Patients of the first group (n = 55) underwent CAG before AAA resection and, if significant stenosis of coronary arteries was detected, revascularization of the myocardium was performed. In patients of the second group (n = 71), only functional cardiac tests were conducted before the operation. Patients of the third group were operated on without additional evaluation of cardiac status. RESULTS: In 30.9% of patients of the first group, significant coronary lesions were detected, in 29.5% of them with the involvement of the left main coronary artery. This required 10 percutaneous coronary interventions and 5 coronary artery bypass surgeries, which made 27.0% of patients in this group. No cases of myocardial infarction were recorded in this group. In the second and third groups, one case of myocardial infarction in each group was recorded (p = 0.688). There was no significant difference in the postoperative mortality in all the groups (1.8%; 4.2%; 2.5%, respectively; p = 0.704). To this end, maximally invasive diagnostic tactics increased the average waiting time for AAA resection: 52.2 ± 6.0 days in groups without coronary angiography and myocardial revascularization versus 99.2 ± 13.0 days in the first group. CONCLUSION: In a cohort of patients without anamnestic and clinical manifestations of coronary artery disease, the tactics of routine coronary angiography followed by prophylactic myocardial revascularization did not improve the short-term results of AAA resection, while the waiting period for intervention on the abdominal aorta increased. Preoperative tactics with functional cardiac tests also did not affect the treatment results.